Poster Presentation Asia-Pacific Vaccine and Immunotherapy Congress 2026

High pre-therapy levels of antibody Fc receptor engagement are associated with better outcomes in patients hospitalised with COVID-19 (#146)

Stephen J Kent 1 , Win Min Han 2 , Kevin J Selva 1 , Amy W Chung 1 , Mark Polizzotto 3 , Cavan Reilly 4 , Sean Liu 5 , Zaiyah Habib 6 , Sarah Pett 7 , Jens-Ulrik Stæhr Jensen 8 , Anthony Keller 2 , Hillary A Vanderven 9
  1. University of Melbourne, Melbourne
  2. Kirby Institute, University of New South Wales, Sydney
  3. Australian National University, Canberra
  4. University of Minnesota , Minneapolis
  5. Icahn School of Medicine at Mount Sinai, New York City
  6. Institute of Human Virology, Abuja
  7. Medical Research Council Clinical Trial Unit at the University College of London, London
  8. Copenhagen University Hospital – Herlev and Gentofte, Hellerup
  9. James Cook University, Douglas, QUEENSLAND, Australia

Neutralising monoclonal antibodies can prevent and treat COVID-19 if administered early after infection with sensitive SARS-CoV-2 variants. Despite containing reasonable levels of neutralising antibodies (1098-1593 IU/mL), hyperimmune intravenous immunoglobulin (hIVIG) failed to mitigate severe COVID-19 in a recent trial in hospitalised patients (NCT04546581). We probed potential reasons for this discrepancy. Based on previous work on human influenza A, we hypothesised that higher baseline spike (S) antibody-specific Fc gamma receptor (FcγR) engagement may promote inflammation and lead to poorer clinical outcomes. We focused on S-specific FcγRIIIa binding activity, a surrogate of antibody-dependent cellular cytotoxicity (ADCC), in pre-treatment serum samples from 481 subjects (n = 231 placebo vs. n = 250 hIVIG). We found that elevated levels of FcγRIIIa engagement by baseline S-specific antibody were associated with better outcomes in patients hospitalised with COVID-19, which was the opposite of our primary hypothesis. Associations between better clinical outcome and high baseline ADCC activity were consistent in both the hIVIG- and placebo-treated groups. Higher nucleocapsid (N) antibody-mediated FcγR engagement and surrogate neutralising activity in pre-treatment sera were also modestly associated with improved clinical outcomes in hospitalised COVID-19 patients. The high prevalence of pre-therapy FcγR binding antibody at hospitalisation, along with the rapid production of these antibodies in placebo-treated subjects, may dilute any potential benefit from hIVIG therapy in patients hospitalised with COVID-19. This work could help guide development of more strategic and targeted treatment of severe SARS-CoV-2 infection with antibody-based therapeutics.